Use of surrogate endpoints in healthcare policy : proposal for consistent adoption of a validation framework

We propose a three step framework for the evaluation of surrogate endpoints for health policy decisions on health technologies

Antidepressant treatment among social workers, human service professionals, and non-human service professionals : A multi-cohort study in Finland, Sweden and Denmark

Background: Social workers have an elevated risk for mental disorders, but little is known about their antidepressant treatment. Aims: To examine any and long-term antidepressant treatment among social workers in Finland, Sweden and Denmark. Methods: We linked records from drug prescription registers to three prospective cohorts: the Finnish Public Sector study, years 2006-2011, and nation-wide cohorts in Sweden and Denmark, years 2006-2014, including a total of 1.5 million employees in (1) social work, (2) other social and health care professions, (3) education and (4) office work. We used Cox proportional hazards models to estimate hazard ratios for any and long-term (>6 months) antidepressant treatment among social workers compared to the three reference occupational groups and carried out meta-analyses. Results: During follow-up, 25% of social workers had any prescriptions for antidepressants (19-24% reference occupations) and 20% for long-term treatment (14-19% reference occupations). The pooled effects for any and long-term treatment showed that probabilities were 10% higher in social workers compared to other health and social care professionals and 30% higher compared to education and non-human service professionals. Probabilities for any treatment in the three countries were relatively similar, but for long-term treatment social workers in Finland had a greater risk compared with other human service professions. Limitations: There were differences between the cohorts in the availability of data. Specific diagnoses for the antidepressant treatment were not known neither adherence to treatment. Conclusion: Social workers have a higher risk for any and long-term antidepressant treatment than other human and non-human service professionals.Peer reviewe

Symbiotic Legume Nodules Employ Both Rhizobial Exo- and Endo-Hydrogenases to Recycle Hydrogen Produced by Nitrogen Fixation

BACKGROUND: In symbiotic legume nodules, endosymbiotic rhizobia (bacteroids) fix atmospheric N(2), an ATP-dependent catalytic process yielding stoichiometric ammonium and hydrogen gas (H(2)). While in most legume nodules this H(2) is quantitatively evolved, which loss drains metabolic energy, certain bacteroid strains employ uptake hydrogenase activity and thus evolve little or no H(2). Rather, endogenous H(2) is efficiently respired at the expense of O(2), driving oxidative phosphorylation, recouping ATP used for H(2) production, and increasing the efficiency of symbiotic nodule N(2) fixation. In many ensuing investigations since its discovery as a physiological process, bacteroid uptake hydrogenase activity has been presumed a single entity. METHODOLOGY/PRINCIPAL FINDINGS: Azorhizobium caulinodans, the nodule endosymbiont of Sesbania rostrata stems and roots, possesses both orthodox respiratory (exo-)hydrogenase and novel (endo-)hydrogenase activities. These two respiratory hydrogenases are structurally quite distinct and encoded by disparate, unlinked gene-sets. As shown here, in S. rostrata symbiotic nodules, haploid A. caulinodans bacteroids carrying single knockout alleles in either exo- or-endo-hydrogenase structural genes, like the wild-type parent, evolve no detectable H(2) and thus are fully competent for endogenous H(2) recycling. Whereas, nodules formed with A. caulinodans exo-, endo-hydrogenase double-mutants evolve endogenous H(2) quantitatively and thus suffer complete loss of H(2) recycling capability. More generally, from bioinformatic analyses, diazotrophic microaerophiles, including rhizobia, which respire H(2) may carry both exo- and endo-hydrogenase gene-sets. CONCLUSIONS/SIGNIFICANCE: In symbiotic S. rostrata nodules, A. caulinodans bacteroids can use either respiratory hydrogenase to recycle endogenous H(2) produced by N(2) fixation. Thus, H(2) recycling by symbiotic legume nodules may involve multiple respiratory hydrogenases

Follow-up observations at 16 and 33 GHz of extragalactic sources from WMAP 3-year data: I - Spectral properties

We present follow-up observations of 97 point sources from the Wilkinson Microwave Anisotropy Probe (WMAP) 3-year data, contained within the New Extragalactic WMAP Point Source (NEWPS) catalogue between declinations of -4 and +60 degrees; the sources form a flux-density-limited sample complete to 1.1 Jy (approximately 5 sigma) at 33 GHz. Our observations were made at 16 GHz using the Arcminute Microkelvin Imager (AMI) and at 33 GHz with the Very Small Array (VSA). 94 of the sources have reliable, simultaneous -- typically a few minutes apart -- observations with both telescopes. The spectra between 13.9 and 33.75 GHz are very different from those of bright sources at low frequency: 44 per cent have rising spectra (alpha < 0.0), where flux density is proportional to frequency^-alpha, and 93 per cent have spectra with alpha < 0.5; the median spectral index is 0.04. For the brighter sources, the agreement between VSA and WMAP 33-GHz flux densities averaged over sources is very good. However, for the fainter sources, the VSA tends to measure lower values for the flux densities than WMAP. We suggest that the main cause of this effect is Eddington bias arising from variability.Comment: 12 pages, 13 figures, submitted to MNRA

Curated genome annotation of Oryza sativa ssp. japonica and comparative genome analysis with Arabidopsis thaliana

We present here the annotation of the complete genome of rice Oryza sativa L. ssp. japonica cultivar Nipponbare. All functional annotations for proteins and non-protein-coding RNA (npRNA) candidates were manually curated. Functions were identified or inferred in 19,969 (70%) of the proteins, and 131 possible npRNAs (including 58 antisense transcripts) were found. Almost 5000 annotated protein-coding genes were found to be disrupted in insertional mutant lines, which will accelerate future experimental validation of the annotations. The rice loci were determined by using cDNA sequences obtained from rice and other representative cereals. Our conservative estimate based on these loci and an extrapolation suggested that the gene number of rice is ~32,000, which is smaller than previous estimates. We conducted comparative analyses between rice and Arabidopsis thaliana and found that both genomes possessed several lineage-specific genes, which might account for the observed differences between these species, while they had similar sets of predicted functional domains among the protein sequences. A system to control translational efficiency seems to be conserved across large evolutionary distances. Moreover, the evolutionary process of protein-coding genes was examined. Our results suggest that natural selection may have played a role for duplicated genes in both species, so that duplication was suppressed or favored in a manner that depended on the function of a gene

Prioritizing sleep for healthy work schedules

Good sleep is advantageous to the quality of life. Sleep-related benefits are particularly helpful for the working class, since poor or inadequate amounts of sleep degrade work productivity and overall health. This review paper explores the essential role of sleep in healthy work schedules and primarily focuses on the timing of sleep in relation to the work period (that is, before, during and after work). Data from laboratory, field and modeling studies indicate that consistent amounts of sleep prior to work are fundamental to improved performance and alertness in the workplace. In addition, planned naps taken during work maintain appropriate levels of waking function for both daytime and night-time work. Clearly, sufficient sleep after work is vital in promoting recovery from fatigue. Recent data also suggest that the time interval between shifts should be adjusted according to the biological timing of sleep. Although sleep is more likely to be replaced by job and other activities in the real life, research shows that it is worthwhile to revise the work schedules in order to optimize sleep before, sometime during and after the work period. Therefore, we suggest establishing work-sleep balance, similar to work-life balance, as a principle for designing and improving work schedules

Distance to high-voltage power lines and risk of childhood leukemia:An analysis of confounding by and interaction with other potential risk factors

We investigated whether there is an interaction between distance from residence at birth to nearest power line and domestic radon and traffic-related air pollution, respectively, in relation to childhood leukemia risk. Further, we investigated whether adjusting for potential confounders alters the association between distance to nearest power line and childhood leukemia. We included 1024 cases aged <15, diagnosed with leukemia during 1968-1991, from the Danish Cancer Registry and 2048 controls randomly selected from the Danish childhood population and individually matched by gender and year of birth. We used geographical information systems to determine the distance between residence at birth and the nearest 132-400 kV overhead power line. Concentrations of domestic radon and traffic-related air pollution (NOx at the front door) were estimated using validated models. We found a statistically significant interaction between distance to nearest power line and domestic radon regarding risk of childhood leukemia (p = 0.01) when using the median radon level as cut-off point but not when using the 75th percentile (p = 0.90). We found no evidence of an interaction between distance to nearest power line and traffic-related air pollution (p = 0.73). We found almost no change in the estimated association between distance to power line and risk of childhood leukemia when adjusting for socioeconomic status of the municipality, urbanization, maternal age, birth order, domestic radon and traffic-related air pollution. The statistically significant interaction between distance to nearest power line and domestic radon was based on few exposed cases and controls and sensitive to the choice of exposure categorization and might, therefore, be due to chance

The contribution of embarrassment to phobic dental anxiety: a qualitative research study

BACKGROUND: Embarrassment is emphasized, yet scantily described as a factor in extreme dental anxiety or phobia. Present study aimed to describe details of social aspects of anxiety in dental situations, especially focusing on embarrassment phenomena. METHODS: Subjects (Ss) were consecutive specialist clinic patients, 16 men, 14 women, 20–65 yr, who avoided treatment mean 12.7 yr due to anxiety. Electronic patient records and transcribed initial assessment and exit interviews were analyzed using QSR"N4" software to aid in exploring contexts related to social aspects of dental anxiety and embarrassment phenomena. Qualitative findings were co-validated with tests of association between embarrassment intensity ratings, years of treatment avoidance, and mouth-hiding behavioral ratings. RESULTS: Embarrassment was a complaint in all but three cases. Chief complaints in the sample: 30% had fear of pain; 47% cited powerlessness in relation to dental social situations, some specific to embarrassment and 23% named co-morbid psychosocial dysfunction due to effects of sexual abuse, general anxiety, gagging, fainting or panic attacks. Intense embarrassment was manifested in both clinical and non-clinical situations due to poor dental status or perceived neglect, often (n = 9) with fear of negative social evaluation as chief complaint. These nine cases were qualitatively different from other cases with chief complaints of social powerlessness associated with conditioned distrust of dentists and their negative behaviors. The majority of embarrassed Ss to some degree inhibited smiling/laughing by hiding with lips, hands or changed head position. Secrecy, taboo-thinking, and mouth-hiding were associated with intense embarrassment. Especially after many years of avoidance, embarrassment phenomena lead to feelings of self-punishment, poor self-image/esteem and in some cases personality changes in a vicious circle of anxiety and avoidance. Embarrassment intensity ratings were positively correlated with years of avoidance and degree of mouth-hiding behaviors. CONCLUSIONS: Embarrassment is a complex dental anxiety manifestation with qualitative differences by complaint characteristics and perceived intensity. Some cases exhibited manifestations similar to psychiatric criteria for social anxiety disorder as chief complaint, while most manifested embarrassment as a side effect

An Integrative -omics Approach to Identify Functional Sub-Networks in Human Colorectal Cancer

Emerging evidence indicates that gene products implicated in human cancers often cluster together in “hot spots” in protein-protein interaction (PPI) networks. Additionally, small sub-networks within PPI networks that demonstrate synergistic differential expression with respect to tumorigenic phenotypes were recently shown to be more accurate classifiers of disease progression when compared to single targets identified by traditional approaches. However, many of these studies rely exclusively on mRNA expression data, a useful but limited measure of cellular activity. Proteomic profiling experiments provide information at the post-translational level, yet they generally screen only a limited fraction of the proteome. Here, we demonstrate that integration of these complementary data sources with a “proteomics-first” approach can enhance the discovery of candidate sub-networks in cancer that are well-suited for mechanistic validation in disease. We propose that small changes in the mRNA expression of multiple genes in the neighborhood of a protein-hub can be synergistically associated with significant changes in the activity of that protein and its network neighbors. Further, we hypothesize that proteomic targets with significant fold change between phenotype and control may be used to “seed” a search for small PPI sub-networks that are functionally associated with these targets. To test this hypothesis, we select proteomic targets having significant expression changes in human colorectal cancer (CRC) from two independent 2-D gel-based screens. Then, we use random walk based models of network crosstalk and develop novel reference models to identify sub-networks that are statistically significant in terms of their functional association with these proteomic targets. Subsequently, using an information-theoretic measure, we evaluate synergistic changes in the activity of identified sub-networks based on genome-wide screens of mRNA expression in CRC. Cross-classification experiments to predict disease class show excellent performance using only a few sub-networks, underwriting the strength of the proposed approach in discovering relevant and reproducible sub-networks